This invention relates to a method of reducing intraocular pressure (IOP) and treating glaucoma in mammals. More specifically, a combination of a cholinergic receptor agonist, also referred to as a cholinomimetic agent, such as pilocarpine, and a cholinergic M.sub.3 receptor antagonist, such as 4-diphenyl-acetoxy-N-methylpiperidine (4-DAMP), topically applied to the eye of a mammal, can be used to reduce elevated IOP without causing the miotic effect that normally accompanies administration of a cholinomimetic agent alone.
Glaucoma refers to a group of diseases of the eye which are characterized by abnormally high intraocular pressure. The outer shell of the eyeball is made up of three coats: a tough outer fibrous tunic composed of variously arranged connective tissue fibers, the uveal tunic and the retina. The choroid is the posterior segment of the uveal tunic. The anterior part of the uvea, in part, is referred to as the ciliary body and is lined with two epithelial cell layers which secrete the aqueous humor which fills the anterior chamber of the eye. In a healthy eye the humor flows from the ciliary body through the pupil into the anterior chamber of the eye and leaves the eye through Schlemm's canal. The rate of formation and the rate of exit of this aqueous humor determines the intraocular pressure in the eyeball.
In subjects suffering from glaucoma the rate of elimination of aqueous humor from the eye is reduced which results in fluid build up within the eye and increased intraocular pressure. If high intraocular pressure is allowed to continue untreated it interferes with the blood supply to the nerve fibers of the retina and optic nerve and if left uncorrected the optic nerve dies and blindness results.
Glaucoma can be treated both through surgery or therapeutically with drugs. Surgery seeks to create new outlets for the aqueous humor and thereby reduce the intraocular pressure. A number of drugs have been discovered which, when either taken internally or applied topically to the eye, lower intraocular pressure but many are toxic and cause undesirable side effects, especially when used as chronic therapy.
Cholinomimetic agents, as exemplified by pilocarpine, are useful antiglaucoma agents which lower IOP by increasing aqueous humor outflow facility. However, their use is associated with numerous side effects, of which miosis and accommodation are the most serious. Zimmerman, T. J. and Wheeler, T. M., Miotics: Side Effects and Ways to Avoid Them, Ophthalmology 89: 76 (1982). A drug or drug combination which acted by a similar mechanism of action as pilocarpine but which did not cause miosis would represent a significant advance in the treatment of glaucoma.
Now with the present invention there is provided a novel method of treatment for elevated IOP which allows a cholinomimetic agent such as pilocarpine to be used to lower IOP without an accompanying miotic effect. The novel method of this invention comprises topical administration of a cholinergic M.sub.3 receptor antagonist, such as 4-DAMP, in combination with a cholinomimetic agent to the eye of a mammal in need of such treatment.
It is generally agreed on the basis of pharmacological studies that cholinergic muscarinic receptors exist in a variety of subtypes. Mitchelson, F., Muscarinic Receptor Differentiation, Pharmacol. Ther. 37: 357 (1988). The cholinergic antagonist 4-DAMP has been shown to selectively block the M.sub.3 (also known as M.sub.2 beta or M.sub.2 glandular) receptor subtype in in vivo studies. Doods, H. N., et al., Selectivity of Muscarinic Antagonists in Radioligand and in Vivo Experiments for the Putative M.sub.1, M.sub.2 and M.sub.3 Receptors, J. Pharmacol. Exp. Ther. 242: 257-262 (1987). The terms "cholinergic M.sub.3 receptor antagonist" and "M.sub.3 antagonist" have the same meaning and will be used interchangeably herein.
When administered alone to the eye of an African Green monkey with elevated IOP, 4-DAMP causes mydriasis of the pupil as shown in FIG. 2, but has no appreciable effect on IOP, as shown in FIG. 1. Administration of pilocarpine alone produces a reduction in IOP FIG. 1), accompanied by a profound miosis (FIG. 2). However, when 4-DAMP is instilled in the eye one hour prior to pilocarpine administration, the 4-DAMP completely prevents the miotic effect of pilocarpine (FIG. 2) without affecting pilocarpine's action upon IOP (FIG. 1).